Marlene Cimons is a freelance writer in Bethesda, Md.

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The Quest for Safe, Effective Blood Substitutes Heats Up

Pathogen-free, immune-compatible, synthetic oxygen-carrying products could be a boon, particularly where blood safety is at issue

Marlene Cimons

Last April, South Africa made medical history by being the first country to approve a blood substitute for human use—Hemopure, made by Biopure Corp. of Cambridge, Mass. While approval of the first generation of blood supplements could be several years away in the United States—where the blood supply is regarded as extremely safe—the availability of such products in a widening array of countries throughout the developing world, where blood often is tainted with infectious agents, could come much sooner and brings with it profound implications.

The licensing of artificial blood products as pathogen-free alternatives to red blood cell transfusion could help lead to a transformation in the health-care landscape of the developing world, where "blood transfusion is the great unwritten tragedy," says Harvey Klein, chief of the department of transfusion medicine at the National Institutes of Health (NIH) Clinical Center in Bethesda, Md. "There is very little blood available in most developing countries, and what there is generally is highly infectious and frequently untested."

In Some Settings, Safe Blood Products Reduce Incentives for Substitutes

For several decades scientists have chased the dream of artificial blood—seeking a product that would be safe, universally compatible, and readily available. A handful of U.S. companies is rapidly making progress toward that goal—despite having available screening and testing procedures that dramatically improve the overall safety of blood and blood products.

"The major question...in the United States is the relative safety [of synthetic] compared to [natural] blood transfusions," says William D. Hoffman, director of the cardiac surgical intensive care unit at Massachusetts General Hospital in Boston, who has studied blood substitutes and, for a time, worked for Biopure. "If you have a bag of blood in one hand and a blood substitute in the other, you'd decide which one worked and which one was safest, and, in this country, it would be the blood."

But the context is dramatically different in countries throughout the developing world, where "there is an enormous need" for safer synthetic products, Klein says. "It will decrease the risk of infection—AIDS, hepatitis B and C—which, even taken together, are relatively small risks [from the blood supply] in the United States."

In the developing world, the number one cause of bleeding death is childbirth, with malaria-related anemia in children second, followed by trauma. Malaria, for instance, kills up to 2.7 million people annually, 90% of them African children younger than five (see Current Topics, p. 496). In the United States, however, the outlook for synthetic blood is less certain, although the science continues to advance and its proponents insist there is a place for it here: particularly, for example, in trauma, in surgery, on the battlefield, and in those patients who cannot or will not accept transfusions of human blood.

And even though donated blood is routinely screened for pathogens, such as HIV and the hepatitis B and C viruses, there is rising concern about other agents, such as the prions believed responsible for causing the new variant of Creutzfeldt-Jakob, or "mad cow" disease, and additional infectious agents that could be introduced into the blood supply. Having artificial blood available also could help ease chronic blood shortages experienced throughout the United States, particularly during times of natural disaster, experts say.

Linda Chambers, senior medical officer for the American Red Cross, believes artificial blood could help her organization and others in dealing with chronic blood shortages nationwide. It would also free up large quantities of blood maintained in long-term storage in thousands of small hospitals that do not ordinarily perform surgery and usually do not handle many emergencies, but keep such stocks on hand, just in case such needs unexpectedly arise.

"We have a lot of blood in refrigerators in small hospitals that doesn't get used," Chambers says. "They could store the artificial blood instead, and the donated blood could get to where it's really needed. It could make a big difference."

Synthetic Blood Designed To Meet Limited Medical Needs

A sample packet of Hemopure, an artificial blood product recently approved for human use in South Africa. (AP Photo/Themba Hadebe.)

Experts believe that synthetic blood could prove particularly useful in several lifesaving and emergency situations by preventing shock. Medical experts in the military anticipate its usefulness on the battlefield. And it also might overcome some of the compunctions among those who refuse transfused natural blood for ethical reasons, such as Jehovah's Witnesses, and among patients with rare blood types or with incompatibilities such as sickle cell anemia, whose needs often prove difficult to meet. Unlike donated blood, synthetic blood does not need to be matched to a recipient's blood type, has a relatively long shelf life, and, depending on formulation, can be stored at room temperature.

Synthetic blood, however, is not expected to replace the real thing. Its main limitation is that it is designed to perform only the task ordinarily carried out by red blood cells (RBCs), namely distributing oxygen throughout the body, and does not and cannot perform most of the other functions that normal blood does. It also does not last very long in the body, making it useful primarily as a stopgap during emergencies, but less valuable as a long-term therapeutic or genuine substitute for RBCs.

Moreover, although safer than natural blood because most synthetic products do not carry infectious disease agents, several potential safety problems are associated with these blood products. For instance, there is some evidence that several of the experimental products being developed and tested can elevate blood pressure, lead to stroke, or induce cardiac arrest.

Several Synthetic Products Are Being Developed

Artificial blood products may find their way into use in emergency trauma treatment in developed countries, but at present one barrier to their acceptance is ready availability of safe blood for other types of procedures. (Richard Olivier/Corbis.)

Several synthetic blood products are currently under development. They fall into two major types. One group starts with a hemoglobin base from animals or humans, and then modifies that molecule to make it more efficient than are ordinary red cells carrying oxygen. The second group starts with a class of synthetic compounds known as perfluorocarbons, which soak up oxygen, but do not bind it so tightly as does hemoglobin, meaning that the oxygen is more readily released to tissues when the synthetic carrier flows through the body.

The experimental products include:

• Biopure's product, Hemopure, that is made from the hemoglobin of beef cattle. Each unit consists of 30 grams of extracted hemoglobin that is purified, chemically cross-linked, and formulated in 250 milliliters of a balanced salt solution. These stabilized, noncellular hemoglobin molecules circulate in plasma with lower viscosity and more readily releasable oxygen; thus, they can carry oxygen at low pressure through constricted or partially blocked blood vessels. South African officials approved Hemopure for treating adult surgical patients who are acutely anemic and for the purpose of eliminating, delaying, or reducing the need for donated blood.

• Hemolink, being developed by Hemosol of Toronto, Ontario, Canada, consists of a highly purified human-derived hemoglobin replacement product that is designed to provide immediate and safe oxygen delivery to vital organs and tissues. In mid-2000, the company filed an application with Canadian regulatory authorities to license this product as a means for avoiding or reducing the use of donor red blood cells in scheduled procedures, such as coronary artery bypass grafting surgery. The outcome of that review is pending.

• PolyHeme, being developed by Northfield Laboratories in Evanston, Ill., also consists of chemically modified hemoglobin derived from human RBCs. The polymerized form is designed to avoid side effects historically associated with hemoglobin-based blood substitutes, including vasoconstriction, kidney dysfunction, liver dysfunction, and gastrointestinal distress. Northfield recently submitted an application to the Food and Drug Administration (FDA) for approval of its product, the first in the field to do so in the United States.

• A blood substitute called Oxygent, being developed by Alliance Pharmaceutical Corp., of San Diego, Calif., is a perflubron emulsion, intravascular oxygen carrier that is intended to reduce the need for donor blood. Although Oxygent treatment provided a statistically significant reduction and avoidance of donor blood usage in a Phase III study of general surgery patients, a separate Phase III study involving cardiac surgery patients was suspended voluntarily earlier this year due to adverse events that the companies now report were not directly related to the product, but from procedures specified in the protocol.

• Sonus Pharmaceuticals of Seattle, Washington, is developing S-9156, a stabilized fluorocarbon gas microbubbles-based oxygen-carrying product that the company says can be used at a "substantially lower dose" than is required with competing liquid fluorocarbon-based oxygen delivery products that are under development.

First Applications Eyed for Surgery, Trauma, Other Emergency Uses

"The field is really at a very advanced stage, the last stages of development," says Abdu I. Alayash, who heads the research program on blood substitutes for the FDA. "There is a real excitement." With some of these products well into clinical trials, applications for FDA evaluation and potential licensing are expected during the summer of this year.

The major focus of several initial clinical studies has been in surgery, although Northfield has also tested its product in trauma patients. Trauma, however, has proven very difficult to study because the situations are often medically complicated, making it difficult to draw valid conclusions. Nevertheless, many experts believe that trauma and other medical emergencies associated with treating heart attack and stroke patients will ultimately prove to be the most valuable setting for these products in this country.

"I envision every ambulance is going to be carrying this," says Aryeh Shander, executive medical director of the New Jersey Institute for the Advancement of Bloodless Medicine, referring generally to synthetic blood products. "If we are convinced it will help in trauma mortality, then clearly it will be a first-line treatment." However, none of the current products is likely initially to be licensed in the U.S. for trauma. Instead, a much narrower indication is expected.

Richard K. Spence, a researcher who studied artificial blood versions during the 1980s, recalls a heart attack victim some years ago—a former boxer in his 50s—who was given a blood substitute as part of a study at Cooper Hospital, Camden, N.J. The idea was to try to prevent heart muscle damage that occurs when the organ is deprived of oxygen. "He was having chest pain; he was in trouble," says Spence, who is now director of surgical education at Baptist Health Systems, Birmingham, Ala. "We got him into bed, and put all the lines in .Within an hour, his pain was gone; his EKG was normal; he sat up, pulled out his IVs, and went out into the waiting room to watch the [Super Bowl] game."

Some Experts Are Skeptical about Acceptability of Synthetic Blood Products

Not everyone believes that artificial blood products will be a medical hit with patients, physicians, and U.S. regulatory officials. For one thing, the products likely will be expensive and complicated to use, according to Keith Berman, the Los Angeles-based editor of a blood products newsletter. "There is no meaningful U.S. market for these agents in elective surgery," he asserts. However, he acknowledges that they might prove useful as "a transient oxygen-supplying `bridge' in massively bleeding patients where there are problems getting access to enough red blood cells or, in rare cases, where patients reject all types of donor blood."

Because the U.S. blood supply is generally very safe, any risks from the uses of synthetic blood need to be taken very seriously before any products are licensed, according to some experts. Thus, Berman and others express concerns about the safety of such products, which only have been studied in a small number of people. Already some worrisome questions have been raised. For example, experimental products sometimes raise blood pressure among users, and experimental uses of other products might have contributed to cardiac problems and strokes among some recipients.

Meanwhile, several other synthetic blood products, namely those that use hemoglobin as a base, can bind nitric oxide, a smooth muscle relaxant produced naturally by the body. Ordinarily, that nitric oxide usefully gobbles free radicals and thus can protect tissues and organs against damage. Some researchers speculate, for example, that when some of these synthetic products sop up nitric oxide, they may be also elevating blood pressure among some patients.

"These products are delivering oxygen by a totally different mechanism as red cells in the blood," Klein of the NIH says. "But we don't know yet what this means physiologically."

An earlier attempt to study artificial blood in trauma proved problematic and was halted. In the mid-1990s, Baxter Healthcare's blood substitute product appeared to be a leading candidate for FDA approval. But the company abruptly stopped the trial after an unexpectedly high number of recipients, 24 of 52, died. "Trauma trials are very difficult trials to do," Klein says. "I give Baxter credit for trying, but it's a very difficult area to study. I think most people feel that it's foolish to study trauma at this point."

With all these misgivings, however, many experts consider the development of oxygen-carrying blood substitutes worth pursuing. They also expect future products to be increasingly fine-tuned to eliminate current problems and side effects. If researchers did not believe this was possible, "they wouldn't have invested such time and effort over all these years," says FDA's Alayash.